Intraneuronal Aβ, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer’s disease

Crowther, Damian C.; Kinghorn, Kerri J.; Miranda, Elena; Page, Richard; Curry, J.A.; Duthie, Fiona; Gubb, David; Lomas, David A.

doi:10.1016/j.neuroscience.2004.12.025

Cited by 328 publications

(424 citation statements)

References 47 publications

Supporting

Mentioning

387

Contrasting

Unclassified

Order By: Relevance

“…Specifically, it reconciles the known extracellular deposition of terminal amyloid plaques in AD patients or AD mouse models (15, 23) with numerous observations from AD patients (33), AD mouse models (34) and Aβ-transgenic Drosophila melanogaster flies (35) showing that Aβ species may also accumulate inside the cell, including MVBs (16,36,37), lysosomes or other vesicular compartments (38)(39)(40). The present observation of an intracellular route of amyloid plaque formation is consistent with observations that extracellular amyloid plaques typically contain a spectrum of proteins that are originally intracellular.…”

Section: Discussionmentioning

confidence: 54%

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Friedrich

Tepper²,

Rönicke³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

284

220

View full text Add to dashboard Cite

The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer’s disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Aβ peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer’s Aβ amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis- or phagocytosis-competent cells. Internalized Aβ peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of Aβ is attributed, at least in part, to intracellular aggregates.

show abstract

Section: Discussionmentioning

confidence: 54%

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Friedrich

Tepper²,

Rönicke³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

284

220

View full text Add to dashboard Cite

show abstract

“…A␤-induced neurodegeneration was seen in areas affected in AD, such as the cerebral cortex, hippocampus and amygdala, but was absent in hindbrain and cerebellum of transgenic animals expressing intraneuronal A␤ (16). Similarly, transgenic flies expressing human wild-type or Arctic mutant E22G A␤42 show neurodegeneration proportional to the degree of intraneuronal oA␤ accumulation (17). In addition, microinjection of heterogeneous A␤42 into cultured human primary neurons at 1 pM concentration induced neuronal cell death (18).…”

mentioning

confidence: 99%

Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Pigino

Morfini

Atagi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

195

184

View full text Add to dashboard Cite

The pathological mechanism by which A␤ causes neuronal dysfunction and death remains largely unknown. Deficiencies in fast axonal transport (FAT) were suggested to play a crucial role in neuronal dysfunction and loss for a diverse set of dying back neuropathologies including Alzheimer's disease (AD), but the molecular basis for pathological changes in FAT were undetermined. Recent findings indicate that soluble intracellular oligomeric A␤ (oA␤) species may play a critical role in AD pathology. Real-time analysis of vesicle mobility in isolated axoplasms perfused with oA␤ showed bidirectional axonal transport inhibition as a consequence of endogenous casein kinase 2 (CK2) activation. Conversely, neither unaggregated amyloid beta nor fibrillar amyloid beta affected FAT. Inhibition of FAT by oA␤ was prevented by two specific pharmacological inhibitors of CK2, as well as by competition with a CK2 substrate peptide. Furthermore, perfusion of axoplasms with active CK2 mimics the inhibitory effects of oA␤ on FAT. Both oA␤ and CK2 treatment of axoplasm led to increased phosphorylation of kinesin-1 light chains and subsequent release of kinesin from its cargoes. Therefore pharmacological modulation of CK2 activity may represent a promising target for therapeutic intervention in AD.Alzheimer's disease ͉ Axonal transport ͉ Beta amyloid oligomer ͉ CK2 ͉ Kinesin T he complex functional changes and histopathology of Alzheimer disease (AD) make it one of the most challenging disorders faced by modern medicine. Histopathological hallmarks of AD include distinctive extracellular and intracellular aggregates of amyloid beta (A␤) and tau (1, 2). Synaptic dysfunction and axonopathy appear to be the earliest lesions in AD as corroborated by reduced immunoreactivity of synaptophysin and other synaptic markers in terminal fields of brain-affected areas (3). AD-affected neurons appear to die eventually as a consequence of synaptic dysfunction and loss, following a typical dying-back pattern of neuronal degeneration.The amyloid hypothesis (4), a dominant concept in AD research for many years, has been revised in recent years to include the notion that smaller soluble A␤ aggregates may play an early and significant role in AD. Soluble oligomers of A␤ (oA␤) have been shown to be neurotoxic both in vivo and in vitro (5-7) as well as altering synaptic structure and function (8). Moreover, oA␤ levels correlate with impairments in cognitive function, learning, and memory (9, 10), but the molecular basis of these effects are uncertain. Intracellular A␤ was first described by Wertkin et al. (11). Immunogold electron microscopy showed that intraneuronal A␤ is pre-and postsynaptically enriched in both AD human brain and AD transgenic animal models in association with dystrophic neurites and abnormal synaptic morphology (12)(13)(14). Spatial and temporal analyses of intraneuronal oA␤ accumulation show that it precedes plaque formation in both AD animal models and Down's syndrome patients, suggesting that oA␤ is an early intracellular toxic agent i...

show abstract

“…In recent years, Drosophila models for Alzheimer's disease were developed (Finelli et al, 2004;Greeve et al, 2004;Crowther et al, 2005), and several factors (such as insulindegrading enzyme, apolipoprotein E, oxidative stress) known to be related to Alzheimer's disease were studied with these Drosophila models (Rival et al, 2009;Sarantseva et al, 2009;Sofola et al, 2010;Tsuda et al, 2010;Ling and Salvaterra, 2011). Work from these groups has shown that Drosophila recapitulates several pathological features also seen in Alzheimer's disease.…”

mentioning

confidence: 99%

Toxicity of Alzheimer's disease-associated Aβ peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability

Hua

Munter

Harmeier

et al. 2011

Biological Chemistry

View full text Add to dashboard Cite

Amyloid plaques consisting of aggregated Ab peptide are a hallmark of Alzheimer's disease. Among the different forms of Ab, the one of 42aa length (Ab42) is most aggregationprone and also the most neurotoxic. We find that eye-specific expression of human Ab42 in Drosophila results in a degeneration of eye structures that progresses with age. Dietary supplements of zinc or copper ions exacerbate eye damage. Positive effects are seen with zinc/copper chelators, or with elevated expression of MTF-1, a transcription factor with a key role in metal homeostasis and detoxification, or with human or fly transgenes encoding metallothioneins, metal scavenger proteins. These results show that a tight control of zinc and copper availability can minimize cellular damage associated with Ab42 expression.

show abstract

Intraneuronal Aβ, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer’s disease

Cited by 328 publications

References 47 publications

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Toxicity of Alzheimer's disease-associated Aβ peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability

Contact Info

Product

Resources

About